tbuckley/cabot-search huggingface dataset:
A randomized phase II trial of neoadjuvant chemokine modulation in patients with localized prostate cancer undergoing radical prostatectomy.
Authors: Karan Jatwani, Bailey Farmer, Arya Mariam Roy, Ronald Slomba, Kristopher Attwood, Ellis Glenn Levine, Eric Kauffman, Pawel Kalinski, Khurshid Guru, Dharmesh Gopalakrishnan, Gurkamal S. Chatta
Journal: Journal of Clinical Oncology (2023)

TPS406 Background: Most patients with high or very high risk localized prostate cancer (PCa) experience disease recurrence after radical prostatectomy (RP). Neoadjuvant androgen ablation has not improved high-risk pathological features or recurrence rates after RP. 1 We reported the association between high intratumoral CD8 + T lymphocyte (CTL) density and improved survival post-RP, suggesting clinical benefit from neoadjuvant immunomodulation (NI). 2 Analysis of the tumor immune microenvironment after NI may also provide key insights into potential therapeutic strategies in PCa. CTL/NK/Th1-recruiting chemokines (CCL5, CXCL9 and CXCL10) are downregulated while MDSC/Treg-attracting chemokines (CCL2, CCL22, and CXCL12) are upregulated in human PCa tissue. 3 A large proportion of T cells in PCa are Tregs or dysfunctional CTLs and this immunosuppressive profile may be partly driven by COX-2 upregulation. 4,5 A chemokine modulating regimen (CKM) of rintatolimod (TLR-3 ligand), aspirin (COX-2 inhibitor), and IFN-α favorably reprogrammed the chemokine profile and CTL/Treg ratio in human PCa explants. 3 This combination has demonstrated safety in phase I/II trials across other tumor types, though it is unclear if IFN-α can be omitted without compromising efficacy. 7-8 Methods: This is a three-arm, phase II trial where patients with localized PCa scheduled to undergo RP are randomized in 1:1:1 ratio to a 2-week regimen of neoadjuvant CKM triplet (rintatolimod + aspirin + IFN-α) vs CKM doublet (rintatolimod + aspirin) vs no CKM. Thirty patients will be enrolled to assess CD8 + T cell density in the RP specimen as the primary endpoint. Pathological and PSA responses, surgical margin positivity, and safety/toxicity of the CKM combinations will be secondary endpoints. Pre- and post-treatment density of various infiltrating T cell subtypes, MDSCs, chemokine and chemokine receptor profiles, immune checkpoint expression, immune-regulatory gene expression signatures, and peripheral blood immune cell landscape will be key exploratory endpoints. The trial is currently open with 11 patients enrolled. Clinical trial ID: NCT03899987 . References: 1) Scolieri MJ, J Urol 2000, 2) Clin Oncol 36, 2018: suppl; abstr 5068, 3) Muthuswamy R, Prostate 2016, 4) Sfanos KS, Prostate 2009, 5) Gupta S, Prostate 2000, 6) NCT01545141, 7) NCT02151448, 8) NCT02432378.
Clinical outcomes of patients with bone-predominant metastatic renal cell carcinoma.
Authors: Jinesh S. Gheeya, Mingjia Li, Menglin Xu, Danielle Elise Zimmerman, Katharine A. Collier, Peng Wang, Edmund Folefac, Paul Monk, Amir Mortazavi, Steven K. Clinton, Ming Yin, Yuanquan Yang
Journal: Journal of Clinical Oncology (2023)

703 Background: Bone-predominant metastatic renal cell carcinoma (mRCC) is associated with aggressive biology and poor prognosis. The optimal management of these patients (pts) remains not well-established. While contemporary trials showed the superiority of immune checkpoint inhibitors (ICI) compared to vascular endothelial growth factor tyrosine kinase inhibitors (TKI), these pts were often excluded due to non-measurable disease. mRCC bone metastases show an enhanced angiogenesis gene signature suggesting the potential for greater responses to TKI. We test this hypothesis in a retrospective study comparing treatment outcomes for the first line (1L) TKI versus ICI in pts with bone-predominant mRCC. Methods: Pts with mRCC who received care at the Ohio State University Comprehensive Cancer Center from 1/1/2008 to 6/1/2021 were identified through retrospective chart review. Bone-predominant metastasis was defined as the number of bone metastases &gt; extra-osseous metastases. Pts who had ≥1 cycle of treatment and follow-up scans were evaluated for treatment responses per RECIST 1.1 criteria. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. The comparisons were made between TKI and ICI cohorts, and the significance was determined by logrank test. Pt who received ICI-TKI in 1L were excluded from the survival analysis due to limited N. Results: A total of 335 pts with mRCC were identified, of which 45 (13.4%) had bone-predominant metastasis. Most of the pts (44/45) had clear cell histology. TKI was the 1L intervention for 21 (47%) while 20 (44%) pts received ICI, and 4 (9%) pts received TKI-ICI. TKI and ICI cohorts were similar for International Metastatic RCC Database Consortium (IMDC) Risk (Table). In the TKI cohort, 19 pts had evaluable responses with ORR of 15.7% and SD of 42%. The mPFS was 5.9 months (95% CI 2.8–9), and mOS was 30.4 months (95% CI 3.3–57.6). In the ICI cohort, 16 had evaluable responses with ORR of 6% and SD of 43.8%. The mPFS was 3.4 months (95% CI 0–8.2), and mOS was 19.3 months (95% CI 14.9–23.7). The hazard ratio was 0.58 for PFS and 0.54 for OS, favoring TKI over ICI, although statistical significance was not reached due to the small sample size (p=0.10 and 0.12, respectively). Conclusions: In this single-center retrospective study, pts with bone-predominant mRCC who received TKI compared to ICI as 1L therapy showed improved ORR, PFS, and OS. These results warrant further investigation in larger studies comparing TKI-containing regimen vs ICI doublet. [Table: see text]
<i>CDK12</i> pathogenic mutations in African American and White patients with prostate cancer.
Authors: Elisa M. Ledet, Nicholas Mitsiades, Ellen B. Jaeger, Calvin Y. Chao, A. Oliver Sartor
Journal: Journal of Clinical Oncology (2023)

38 Background: African American (AA) men are underrepresented in prostate cancer (PC) trials but have a greater probability of both developing and dying from prostate cancer (PC) than other populations. CDK12 mutations in PC are associated with aggressive disease, increased metastasis, and decreased overall survival. Some preliminary data has suggested that CDK12 mutations may be more common in AA men. This study reports data from next-generation sequencing (NGS) of tissue from a large population of patients with PC in the real-world setting to investigate frequency of pathogenic CDK12 mutations in AA men and White men. Methods: De-identified records from patients with primary PC who underwent NGS with Tempus xT (solid tumor, 648 genes, 500× coverage, full transcriptome RNAseq for a subset of patients) were analyzed to characterize the frequency and types of pathogenic CDK12 mutations, and co-mutation in other assessed genes. Results were compared between patients identified as AA and White. Patients were excluded if they were Microsatellite Instability high (MSI-H), Tumor Mutational Burden (TMB) ≥10, or Mismatch Repair deficient (MMR-d). Results: Genomic profiles were analyzed from tissue samples of 6121 unique patients; of 3,555 patients with known race, 646 (18%) were AA, 2657 (75%) were White, and 252 (7%) were of other races. Of these patients, 3026 were AA or White after excluding 277 patients with known MSI-H, TMB≥10, or MMR-d status. AA were younger at diagnosis than Whites (median 63 vs 66 years; p&lt;0.001). Tissue samples from AA men were significantly more likely than those from Whites to express a pathogenic CDK12 mutation (42 [7.2%] vs 93 [3.8%], p&lt;0.001). The majority of the variants identified were truncating mutations. There were no differences in truncating vs. non-truncating alterations between White and AA men, nor were there differences in the prevalence or distribution of co-mutations between the two populations. Conclusions: AA men with PC show a higher frequency of pathogenic CDK12 mutations than Whites in a large real-world population. Co-mutations did not vary by race, and the alterations were most likely to be truncating mutations in both races.
Impact of somatic DNA repair mutations on bone-related efficacy endpoints in patients with metastatic castration-resistant prostate cancer (mCRPC): A retrospective analysis.
Authors: Maria Concetta Cursano, Emilio Francesco Giunta, Emanuela Scarpi, Chiara Casadei, Alessandra Virga, Paola Ulivi, Sara Bleve, Nicole Brighi, Giorgia Ravaglia, Francesco Pantano, Daniele Santini, Vincenza Conteduca, Ugo De Giorgi
Journal: Journal of Clinical Oncology (2023)

214 Background: Up to 80% of mCRPC have bone metastases and about 25% of metastatic prostate cancer harbor mutations in DNA damage repair defects (DDR). DDR gene mutations are a negative prognostic factor, being associated with short metastasis-free survival and cancer-specific survival. We analyzed the impact of somatic mutations in DDR genes on bone-related efficacy endpoints in mCRPC. Methods: We retrospectively analyzed the mutational status of mCRPC patients per FoundationOne analysis in tissue biopsy or, when it was not possible, in liquid biopsy (performed at the onset of mCRPC). We evaluated the impact of DDR gene mutations on bone-related efficacy endpoints at the time of mCRPC diagnoses, by dividing patients in two main groups (mutated DDR, specifically, mutations in at least one of BRCA1/2, ATM, FANCA, ATR, CHEK2, RAD51, PALB2, and CDK12 genes: group A; wild-type DDR: group B). We investigated differences between the two groups in terms of time from bone metastases onset to death, skeletal metastatic tumor burden (sites and number of lesions), skeletal-related events (SRE) incidence, and time to first on-study SRE. Results: Of the 131 patients with mCRPC enrolled, 115 had bone metastases. Clinical data distribution, according to molecular profile, is presented. There is no difference in terms of sites of metastases and time from bone metastases onset to death between the 2 groups. Mutated DDR status was associated with bone metastases volume (p = 0.0325), but did not affect SRE incidence and time to SRE onset. Conclusions: In our analysis, mutated DDR status was associated with higher bone metastases volume, although a not detrimental effect on the other bone-related efficacy endpoints was observed. [Table: see text]
Molecular characteristics of advanced clear cell renal cell carcinoma (ccRCC) harboring TERTmutations.
Authors: Nataliya Mar, Ellen B. Jaeger, Arya Ashok, Arash Rezazadeh
Journal: Journal of Clinical Oncology (2023)

706 Background: There is a large unmet need for identifying prognostic and predictive biomarkers in advanced RCC. TERT is a catalytic subunit of the telomerase enzyme and TERT promoter mutations lead to increased telomerase activity, which promotes tumorigenesis by preventing telomere shortening. Emerging data suggests a correlation between TERT promoter mutations (pTERTmut) and improved responses to immune checkpoint inhibitors in urothelial carcinoma (UC), while there is paucity of such data in RCC. This study aims to analyze the immune biomarker environment and co-mutational landscape in TERT mutated versus wild-type RCC. Methods: A retrospective analysis of patients with advanced ccRCC who completed sequencing with the Tempus xT assay (DNA-seq of 648 genes at 500x coverage, full transcriptome RNA-seq) was performed. De-identified data was analyzed for presence of pTERTmut, all other TERT mutations (otherTERT), and TERT wildtype (wtTERT). Companion alterations and immune biomarkers were compared between these three groups. Results: A total of 866 samples was analyzed, with 58% from primary renal lesions and 42% from a metastatic site. The frequency of all TERT mutations was 8.2% (71/866). pTERTmut was present in 5.6% (28/502) of primary and 5.5% (20/364) of metastatic sites, while otherTERT was present in 3.0% (15/502) of primary and 2.2% (8/364) of metastatic sites. Tumor mutational burden (TMB) was performed in 764 samples and only 0.4% had TMB greater than 10 m/MB, all of which were wtTERT. Median TMB was 2.08 m/MB across all samples, with 1.91 m/MB in pTERTmut, 1.72 m/MB in otherTERT, and 2.31 m/MB in wtTERT. Only 0.2% of 834 samples harbored MSI-high and 1.4% of 295 samples were mismatch repair deficient (dMMR), all of which were wtTERT. PD-L1 status was available in 439 samples, with 14% scored as positive (PD-L1+) with a combined positive score &gt;10. Of PD-L1+, 4.8% was in pTERTmut, 3.2% in otherTERT, and 92.1% in wtTERT. Neoantigen tumor burden of all non-silent mutations was evaluated in 698 samples, with a median value of 2.11 in pTERTmut, 1.58 in otherTERT, and 2.11 in wtTERT. PBRM1 co-mutations were noted in 22.9% of samples with pTERTmut, 21.7% in otherTERT, and 33.2% in wtTERT. Additional RCC co-mutations are listed in the table. RCC mRNA and UC cohort data analysis is in progress. Conclusions: This is the largest analysis of the molecular and immune landscape of TERT mutated ccRCC. Interestingly, this dataset showcases that traditional immune biomarkers (TMB, MSI, dMMR, and PD-L1) do not appear to be highly prevalent in RCC and their use in clinical practice may be limited. Further investigation into the TERT biomarker candidate is warranted. [Table: see text]
Safety and efficacy of immune checkpoint inhibitors (ICI) in advanced penile squamous cell carcinoma (PeCa): An international study from the Global Society of Rare Genitourinary Tumors (GSRGT).
Authors: Talal El Zarif, Amin Nassar, Lijuan Jiang, Gregory Russell Pond, Tony Zhuang, Maud Velev, Andrew Warren Hahn, Sebastiano Buti, Pablo Álvarez, Rana R. McKay, Bruno Vincenzi, Edward El-Am, Gavin Hui, Jae-Lyun Lee, Tarek H. Mouhieddine, Matthew I. Milowsky, Harrison Matthews, Pedro C. Barata, Andrea B. Apolo, Guru P. Sonpavde
Journal: Journal of Clinical Oncology (2023)

5 Background: Management options for patients (pts) with advanced (locally advanced or metastatic) PeCa are limited. The GSRGT assembled an international cohort of pts with advanced PeCa treated with ICI to evaluate toxicity and clinical outcomes. Methods: We retrospectively collected data on pts with advanced PeCa receiving ≥1 cycle of ICI between 2015-2022 at 18 medical centers in the US, Europe, and Asia. Immune-related adverse events (irAE) were graded per the Common Terminology Criteria for Adverse Events v5.0. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method. Objective response rate (ORR) was determined by the clinical investigator per RECIST 1.1 criteria, whenever feasible. Results: Among 72 pts with advanced PeCa treated with ICI, 24 (33%) were Hispanic and 7 (10%) were Black. 60 (83%) pts had metastases while the remainder had locally advanced disease. The median age was 64 (inter-quartile range (IQR): 54,70) years and 48 (67%) had ECOG performance status ≥1. Most pts (n=60, 83%) were treated in the ≥2 nd line setting and received pembrolizumab (n=23), nivolumab (n=15), cemiplimab (n=15), nivolumab and ipilimumab (n=7), or other anti-PD1/L1-based therapies (n=12). Among 37 pts with available data on HPV status, 24 (65%) were HPV+. 3 (4%) pts were HIV+. irAE of any grade occurred in 18 (25%) pts, 7 (10%) were grade ≥3, 7 (10%) required steroids, 6 (9%) required hospitalization, and 8 (11%) led to treatment discontinuation. The median OS and 24-month OS and median PFS and 24-month PFS were 9.4 (95%CI: 6.8, 12.8) months and 19.3% (95%CI: 9.2, 32.1) and 2.8 (95%CI: 2.1, 3.9) months and 11.2 % (95%CI: 4.9, 20.2), respectively. Among 66 pts evaluable for response, ORR was 7/66 (11%) (2 with complete response, 5 with partial response), and 16 (24%) pts had stable disease for a disease control rate of 35%. The median duration of response was 7.9 (IQR: 3, not reached) months. Conclusions: In the largest retrospective cohort of ICI-treated advanced PeCa, ICI showed no new safety signals, however, overall anti-tumor activity was limited. Future translational studies are needed to identify pts that are more likely to derive clinical benefit from ICI.
Major adverse cardiovascular event risk following androgen deprivation therapy initiation by personal history of cardiovascular events.
Authors: Andrew Lee, Jacqueline Henry, Stuart Atkinson
Journal: Journal of Clinical Oncology (2023)

351 Background: Associations between androgen deprivation therapy (ADT) and increased cardiovascular (CV) risk in prostate cancer (PCa) patients have been reported; however, how many of these major adverse CV events (MACE) are caused by ADT itself has been debated. One risk factor for increased CV risk is a prior history of CV events; an analysis found that each new CV event increased the probability of a future event. This study aims to evaluate the incidence of MACE after ADT initiation for patients with and without a prior medical history of MACE. Methods: Analyses of US electronic medical records (2010 to 2020) of PCa patients (n=45,059) receiving LHRH agonist and antagonist injections were conducted to evaluate MACE incidence after ADT initiation in patients with and without MACE history. Exclusion criteria included lack of ADT initiation date or myocardial infarction (MI)/stroke within 6 months prior to ADT initiation. MACE was defined as MI, stroke, and death from any cause. Kaplan-Meier event-free survival curves were constructed, and Cox regression was used to compare the MACE hazard rates between patients with and without a personal history of MACE. Multivariate Cox regression adjusted for agonists vs antagonist, increasing age per year, BMI (&lt;18.5 vs ≥18.5 kg/m2), race (White vs Black), family MACE history, ethnicity (Hispanic vs non-Hispanic), urology vs oncology setting, history of hypertension, and history of hypercholesterolemia. Results: Overall, MACE incidence was 3.9% and 19.6% for the cohort at one year and four years after ADT initiation, respectively. MACE risk following ADT initiation was higher for patients with history of prior MACE (unadjusted: (HR=2.76, 95% CI [2.49, 3.06], p&lt;0.001); adjusted: HR=2.29, 95% CI [1.93, 2.71], p&lt;0.001). When MACE was divided into component events, the risks of myocardial infarction and stroke were higher for patients with a prior MACE history compared to those without (8 vs. 1% and 8 vs. 2%, respectively), and the risk of any-cause death was similar (13 vs. 14%). Conclusions: MACE incidence in PCa patients in the first year of ADT was consistent with previous publications.(3). When MACE risk was analyzed in detail, ADT patients with a personal history of stroke or myocardial infarction (MI) had a 4- and 8-fold greater risk of a subsequent stroke and MI, respectively, compared to those without a history of stroke or MI. Given the large sample size (~45,000 PCa patients) of this data set over the recent past decade, these results likely reasonably reflect the real world. Urologists and oncologists should work with cardiologists, cardio-oncologists, and primary care practitioners to ensure the highest quality CV care is delivered.
Evaluation of ctDNA in patients treated with lutetium-177-PSMA-617.
Authors: Sree M Lanka, Albert Jang, Patrick L Sweeney, Kanika Gupta, Sydney Caputo, Crystal Casado, Minqi Huang, Olivia Pocha, Maddie Hawkins, Alexandra Lieberman, Jennifer Schwartz, Ellen B. Jaeger, Patrick Miller, Jodi Lyn Layton, Pedro C. Barata, Brian E. Lewis, Elisa M. Ledet, A. Oliver Sartor
Journal: Journal of Clinical Oncology (2023)

243 Background: Lutetium-177- PSMA-617 (Lu-177) is a radioligand therapy that delivers radiation to PSMA-expressing cells in patients with advanced prostate cancer. In this study, we aimed to analyze ctDNA in responders and non-responders after Lu-177 treatments. Methods: Data was retrospectively collected on 31 heavily pre-treated metastatic CRPC patients who received Lu-177 treatment at Tulane Cancer Center. All patients fulfilled VISION criteria for treatment and all had ctDNA assessment with Guardant 360 within 30 days prior to first treatment with Lu-177. Of the 31 patients, 7 had paired ctDNA assessment both prior initiation of treatment and at the end of treatment. Clinical data such as PSA response (PSA decline 50% or more) to Lu-177, initial diagnosis, pathology, treatment history, and relevant germline genetic data were collected. Results: Of the 31 patients who received Lu-177 treatment, 18 had PSA response to Lu-177 (responders) and 13 did not (non-responders). In ctDNA mutational analyses, there were no significant differences detected prior to treatment between responders and non-responders. There was, however, a significant increase in the presence of copy number amplifications in non-responders (n= 11/13) when compared to responders (n= 7/18) (OR= 8.64, 95% C.I. [1.46, 51.25)], p = 0.0250). Amplification was detected in 10 genes in non-responders, whereas responders only had amplifications in AR (7/18) and EGFR (1/18). The most frequently amplified genes in non-responders were AR (8/13), CCNE1 (6/13), EGFR (4/13), and FGFR1 (4/13). Furthermore, in analysis of the 7 patients with paired ctDNA assessments, amplifications increased during treatment with Lu-177. Conclusions: Radioligand therapy with Lu-177 has been shown to prolong life and reduce disease progression. Our analysis of the cohort of Lu-177 treated patients showed that the presence of gene amplifications in ctDNA may play a role in predicting resistance to treatment with Lu-177.